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A leap in gene function discovery
  
By Haleh V. Samiei

After the sequencing of the human genome comes the daunting task of determining the function of all the unknown genes. The technology for discovering gene function, however, is lagging way behind the advances made for genomic sequencing. A paper in a recent issue of Cell provides just the right example in the kind of leap needed to get up to speed again.


Correlation plot showing gene expression for all 6000 S. cerevisiae genes in response to clotrimazole exposure (horizontal axis) and a randomly chosen gene deletion (rpd3, vertical axis).

Researchers have come up with an assay where it is possible to monitor hundreds of cellular functions all at the same time. They did this by building a "compendium" of gene expression profiles from hundreds of yeast (Saccharomyces cerevisiae) mutants as well as cells exposed to various chemicals.

To make the expression profiles, the researchers took advantage of DNA microarray technology, which involves attaching thousands of samples of DNA corresponding to different genes onto grids on small glass slides. It is then possible to ask which genes are turned on and off in cells under different conditions or with different mutations. Active genes light up and can be read via a computer when fluorescent-labeled complementary DNA corresponding to different cells' gene products are combined with the DNA on the glass slides.


Gene functions can be identified by a compendium of expression profiles

The researchers were able to obtain such patterns of gene expression for 300 mutant yeast cells or normal cells treated with various chemicals and save them in a database similar to those used for fingerprints or mug shots. One can identify the function of new genes or the target of new drugs by obtaining new expression profiles and matching the pattern against the database. The match suggests how a mutation in a new gene or how a chemical treatment affects the function of other genes. From that the researchers are able to infer data about the gene or drug of interest.

The significance of using expression profiles is that—rather than just finding out what a gene of interest does on its own—researchers can determine how the gene interacts with all other genes. The information obtained from chemical treatment of yeast cells may be very important for drug discovery. Current methods take a long time to identify molecular targets of new drugs. Matthew Marton, at Rosetta Inpharmatics, Inc., in Kirkland, Washington, says that the approach used in this paper is not earth-shattering. But, he says, " It is the first demonstration that it can work in terms of finding out how drugs act on cells." He also points out the sensitivity of comparing expression profiles in determining very subtle differences in how cells may respond to similar drugs.


Correlation plot showing gene expression for all 6000 S. cerevisiae genes in response to clotrimazole exposure (horizontal axis) and a titration of the ERG11 gene (vertical axis).

Although this method of expression profiling can also be applied to multi-cellular organisms with another level of complexity from different tissues and developmental stages, certain questions about genes in higher organisms can first be answered much more quickly in yeast. In the Cell paper, the researchers identified the yeast gene erg2 as the target of dyclonine, a topical anaesthetic used in humans. A similar gene exists in humans and is likely to be the target for the drug as well. Although the results would need to be verified in humans, this approach provides a big lead. Marton says, "We can use this as a hypothesis generator for what is happening in mammalian cells."

The amount of data generated from this paper on yeast gene expression is tremendous. At the same time, the researchers only analyzed a small subset of the data. "This paper, in some sense, really scratches the surface or skims the top of the findings in this data set," says Marton. He expects other researchers to be downloading the data set available on the Rosetta Web site (www.rii.com), and continuing to make discoveries in their own research programs.

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Hughes, T.R. et al. Functional discovery via a compendium of expression profiles. Cell 102, 109-126 (July 7, 2000).
 

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